Targeting of cell surface proteins on cancer cells is a modern approach for cancer therapy. Targeted cytotoxins are 5-10 times more potent on cancer cells than chemotherapy and provide specificity without producing undesirable side effects (Frankel, A. E. et al., Cancer Res. 56, 926-932 (1996); Rand, R. W. et al., Clin. Cancer Res. 6, 2157-2165 (2000)). To generate a targeted agent, identification of unique cancer cell-associated receptors or antigens is important.
Recent advances in the development of comprehensive molecular analysis tools for genome and gene expression provide a basis to discover novel target molecules with tumor-specific distribution (Velculescu et al., Science, 270:484-7 (1995)). In previous efforts to identify novel glioma-associated antigens, several genes were found by the serial analysis of gene expression method that are preferentially expressed in gliomas (Loging et al., Genome Res, 10:1393-402 (2000)). Among these candidate glioma-marker genes, glycoprotein nmb (GPNMB) showed a greater than 10-fold induction of mRNA expression over normal brain samples in 5/12 of HGL cases (Loging et al., supra).
Glycoprotein nonmetastatic melanoma protein B (“GPNMB”) is a type I transmembrane protein which was isolated from a subtractive cDNA library based on differential expression between human melanoma cell lines with low and high metastatic potential in nude mice. gpnmb mRNA was also expressed at high levels in low-metastatic melanoma cell lines and xenografts (Wetennan et al., Int J Cancer, 60:73-81 (1995)). Human GPNMB exists both in its native form (“GPNMBwt”) and a splice variant form in which there is a 12-amino acid in-frame insertion in the extracellular domain (“GPNMBsv”)
Immunotoxins have been made that recognize a wide variety of cell-surface targets on cancer cells. Typically these are tumor-associated antigens—i.e., antigens that are overexpressed on cancer cells relative to normal cells. It would be desirable to have immunotoxins useful for inhibiting the growth of cells expressing GPNMB.